Editorial: Community series in new insights into innate immune cell-based immunotherapies in cancer, volume II

@article{porta2026editorial,
  title = {{Editorial: Community series in new insights into innate immune cell-based immunotherapies in cancer, volume II}},
  author = {Chiara Porta and Mary Poupot-Marsan and Virginie Lafont},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = jun,
  doi = {10.3389/fimmu.2026.1898947},
  url = {https://hal.science/hal-05793203v1},
  note = {CC BY},
}

TY  - JOUR
TI  - Editorial: Community series in new insights into innate immune cell-based immunotherapies in cancer, volume II
AU  - Chiara Porta
AU  - Mary Poupot-Marsan
AU  - Virginie Lafont
PY  - 2026
DA  - 2026/06/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1898947
UR  - https://hal.science/hal-05793203v1
AB  - Adaptive T cell-centric immunotherapies, such as immune checkpoint inhibitors (ICIs) and Chimeric Antigen Receptor (CAR) T-cell therapies, have fundamentally transformed clinical oncology. However, the limitations of their therapeutic potential are becoming more evident. Many patients fail to achieve durable responses due to tumorintrinsic escape mechanisms. These challenges include low tumor mutational burden (TMB), loss of human leukocyte antigen (HLA) expression, and an aggressively immunosuppressive tumor microenvironment (TME) that actively excludes or exhausts cytotoxic T cells. To overcome these barriers, the field of immuno-oncology is experiencing a paradigm shift toward harnessing the innate immune system. Innate immune cells, including natural killer (NK) cells, macrophages, dendritic cells, γδ T cells, and other innate-like lineages, possess unique advantages. These cells feature rapid activation kinetics, HLA-independent tumor recognition, high functional plasticity, and a natural capacity to remodel the suppressive TME, thereby orchestrating and rescuing adaptive anti-tumor immunity. Building on the success of the first volume, this Research Topic, "Community Series in New Insights into Innate Immune Cell-Based Immunotherapies in Cancer: Volume II", presents a curated collection of five landmark articles. These contributions span basic, translational, and computational immunology, collectively bridging bench discoveries to next-generation clinical designs.A major hurdle in translating cell-based immunotherapies lies in the scalable manufacturing and genetic engineering of primary immune cells. Standard viral transduction protocols often suffer from low efficiency in NK cells, prompting the search for non-viral alternatives. Addressing the theme of innate cell engineering, Wang et al. establish a highly optimized, nucleofection-based screening platform for CAR candidates in human primary NK cells. By systematically refining transfection parameters and evaluating electroporation conditions, their methodology allows rapid, high-efficiency evaluation of CAR expression and cytotoxicity without the prolonged timelines and safety concerns associated with viral vectors. This protocol provides an agile, bench-to-bedside toolkit to accelerate the preclinical screening of novel CAR-NK constructs.Parallel to cell engineering is the requirement for robust cellular expansion. Adoptive NK-cell therapies frequently require large numbers of functional, non-exhausted effector cells. Giordano et al. address this clinical bottleneck by demonstrating that a CD94-driven in vitro expansion protocol can successfully generate highly functional adaptive NKG2C + NKG2A -CD57 + NK cells from human cytomegalovirus-seropositive (CMV + ) healthy donors. This specific subset displays superior longevity, enhanced cytokine production, and elevated direct cytotoxicity against leukemia and colorectal cancer cells. This work validates an accessible, cost-effective strategy to harvest and amplify high-potency "off-the-shelf" immunotherapeutic products from readily available donor pools.The traditional view of innate immunity as lacking memory has been dismantled by the discovery of "trained immunity", epigenetic and metabolic reprogramming of myeloid and NK cells resulting in long-term, non-specific hyper-responsiveness. In a comprehensive review, Qu et al. examine the biological mechanics and clinical significance of trained immunity in oncology. The authors delineate how trained immune stimulants, such as microbial components (e.g., β-glucans, BCG), can reprogram progenitor cells in the bone marrow to generate long-lasting, tumor-resilient myeloid and lymphoid effectors. They discuss how exploiting this innate immunological memory can complement conventional immune checkpoint blockades and alleviate systemic immunosuppression.In addition to immunological memory, metabolic cross-talk within the TME serves as a critical axis regulating cell function. Tumor cells dynamically rewire their metabolic pathways to survive, which directly impacts surrounding immune cells. Villalba et al. explore this metabolic-signaling cross-talk, highlighting Mitogen-Activated Protein Kinase ERK5 (MAPK ERK5) as a vital nexus. The authors evaluate how tumor-intrinsic fatty acid oxidation (FAO) dictates metastatic potential while simultaneously modulating the activation of ERK5 signaling networks. This pathway fundamentally acts as a molecular "rheostat" that shapes cancer cell susceptibility to NK-mediated immunosurveilllance.Targeting the FAO-ERK5 axis thus represents a promising therapeutic avenue to sensitize resistant tumors to NK-cell effector functions.Designing personalized immunotherapies requires an intimate, spatiotemporal understanding of how the TME changes as a tumor progresses. To profile these dynamics, Hurtado et al. present an advanced computational immunology pipeline, executing transcriptomic profiling of the non-small cell lung cancer (NSCLC) microenvironment across early to advanced disease stages. Crucially, to provide necessary functional validation beyond public database analysis, the authors validate their deconvolution results using independent patient cohorts and single-cell RNAsequencing (scRNA-seq) datasets. Their analysis uncovers "dual immune cell behaviors," revealing specific transcription factor networks that drive innate cells, particularly NK subsets, to transition from active anti-tumor effectors in early-stage disease to exhausted or suppressive states as malignancy progresses. These findings provide a framework for timing innate immunotherapies relative to disease staging.The scientific contributions compiled in this Research Topic underscore the high versatility of innate immune cells in cancer therapy. From non-viral CAR-NK engineering and targeted expansion of potent adaptive NK subsets, to the exploitation of trained immunity, metabolic signaling, and longitudinal microenvironmental…
SN  - 1664-3224
SN  - 1664-3224
ER  -